Update on glycerol-3-phosphate acyltransferases: the roles in the development of insulin resistance

Abstract

Glycerol-3-phosphate acyltransferase (GPAT) is the rate-limiting enzyme in the de novo pathway of glycerolipid synthesis. It catalyzes the conversion of glycerol-3-phosphate and long-chain acyl-CoA to lysophosphatidic acid. In mammals, four isoforms of GPATs have been identified based on subcellular localization, substrate preferences, and NEM sensitivity, and they have been classified into two groups, one including GPAT1 and GPAT2, which are localized in the mitochondrial outer membrane, and the other including GPAT3 and GPAT4, which are localized in the endoplasmic reticulum membrane. GPATs play a pivotal role in the regulation of triglyceride and phospholipid synthesis. Through gain-of-function and loss-of-function experiments, it has been confirmed that GPATs play a critical role in the development of obesity, hepatic steatosis, and insulin resistance. In line with this, the role of GPATs in metabolism was supported by studies using a GPAT inhibitor, FSG67. Additionally, the functional characteristics of GPATs and the relation between three isoforms (GPAT1, 3, and 4) and insulin resistance has been described in this review.

Fig. 1. Glycerophospholipid pathway.

Glycerol-3-phosphate acyltransferase 1 (GPAT1) and GPAT2 are localized in the mitochondrial outer membrane, while GPAT3, GPAT4, phosphatidic acid phosphatase (PAP/lipin), and diacylglycerol acyltransferase (DGAT) are localized in the endoplasmic reticulum (ER) membrane. In addition, 1-acyl glycerol-3-phosphate acyltransferase (AGPAT) is localized in both the mitochondrial outer membrane and the endoplasmic reticulum (ER) membrane. GPATs competitively catalyze acyl-CoA and glycerol-3-phosphate (G3P) to produce lysophosphatidic acid (LPA) and protect acyl-CoA from β-oxidation. Then, LPA and acyl-CoA are converted to phosphatidic acid (PA) by AGPAT. Consequently, PA is dephosphorylated by lipin to diacylglycerols (DAG). DAG and acyl-CoA are catalyzed by DGAT to form triacylglycerol (TAG). Furthermore, TAG synthesizes lipid droplets (LD). The intermediate products (LPA, PA, DAG) are responsible for intercellular signal transduction

Fig. 2. GPAT and insulin resistance.

Glycerol-3-phosphate acyltransferase 1 and 4 (GPAT1 and GPAT4) overexpression impairs insulin signaling in mice. The increased intermediates by GPAT1 activated the PKCε pathway, and phosphatidic acid (PA) produced by overexpression of GPAT1 and GPAT4 interfere with the insulin signaling and inhibit the association between rictor and the mammalian target of rapamycin (mTOR) as well as mTORC2 (mTOR complex) activity in mice, which resulted in insulin resistance and impaired glucose homeostasis